A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice.

Chronic heavy alcohol use is associated with lethal arrhythmias. Whether common East Asian-specific aldehyde dehydrogenase deficiency (ALDH2*2) contributes to arrhythmogenesis caused by low level alcohol use remains unclear. Here we show 59 habitual alcohol users carrying ALDH2 rs671 have longer QT interval (corrected) and higher ventricular tachyarrhythmia events compared with 137 ALDH2 wild-type (Wt) habitual alcohol users and 57 alcohol non-users. Notably, we observe QT prolongation and a higher risk of premature ventricular contractions among human ALDH2 variants showing habitual light-to-moderate alcohol consumption. We recapitulate a human electrophysiological QT prolongation phenotype using a mouse ALDH2*2 knock-in (KI) model treated with 4% ethanol, which shows markedly reduced total amount of connexin43 albeit increased lateralization accompanied by markedly downregulated sarcolemmal Nav1.5, Kv1.4 and Kv4.2 expressions compared to EtOH-treated Wt mice. Whole-cell patch-clamps reveal a more pronounced action potential prolongation in EtOH-treated ALDH2*2 KI mice. By programmed electrical stimulation, rotors are only provokable in EtOH-treated ALDH2*2 KI mice along with higher number and duration of ventricular arrhythmia episodes. The present research helps formulate safe alcohol drinking guideline for ALDH2 deficient population and develop novel protective agents for these subjects.

LCRMP-1 is required for spermatogenesis and stabilises spermatid F-actin organization via the PI3K-Akt pathway.

Long-form collapsin response mediator protein-1 (LCRMP-1) belongs to the CRMP family which comprises brain-enriched proteins responsible for axon guidance. However, its role in spermatogenesis remains unclear. Here we find that LCRMP-1 is abundantly expressed in the testis. To characterize its physiological function, we generate LCRMP-1-deficient mice (Lcrmp-1-/-). These mice exhibit aberrant spermiation with apoptotic spermatids, oligospermia, and accumulation of immature testicular cells, contributing to reduced fertility. In the seminiferous epithelial cycle, LCRMP-1 expression pattern varies in a stage-dependent manner. LCRMP-1 is highly expressed in spermatids during spermatogenesis and especially localized to the spermiation machinery during spermiation. Mechanistically, LCRMP-1 deficiency causes disorganized F-actin due to unbalanced signaling of F-actin dynamics through upregulated PI3K-Akt-mTOR signaling. In conclusion, LCRMP-1 maintains spermatogenesis homeostasis by modulating cytoskeleton remodeling for spermatozoa release.

N-glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC.

Lung cancer is the leading cause of cancer-related death worldwide. As well as the identified role of epidermal growth factor receptor (EGFR), its association with driver mutations has improved the therapeutics for patients with lung cancer harboring EGFR mutations. These patients usually display shorter overall survival and a higher tendency to develop distant metastasis compared with those carrying the wild-type EGFR. Nevertheless, the way to control mutated EGFR signaling remains unclear. Here, we performed membrane proteomic analysis to determine potential components that may act with EGFR mutations to promote lung cancer malignancy. Expression of transmembrane glycoprotein non-metastatic melanoma protein B (GPNMB) was positively correlated with the status of mutated EGFR in non-small-cell lung cancer (NSCLC). This protein was not only overexpressed but also highly glycosylated in EGFR-mutated, especially EGFR-L858R mutated, NSCLC cells. Further examination showed that GPNMB could activate mutated EGFR without ligand stimulation and could bind to the C-terminus of EGFR, assist phosphorylation at Y845, turn on downstream STAT3 signaling, and promote cancer metastasis. Moreover, we also found that Asn134 (N134) glycosylation of GPNMB played a crucial role in this ligand-independent regulation. Depleting N134-glycosylation on GPNMB could dramatically inhibit binding of GPNMB to mutated EGFR, blocking its downstream signaling, and ultimately inhibiting cancer metastasis in NSCLC. Clarifying the role of N-glycosylated GPNMB in regulating the ligand-independent activation of mutated EGFR may soon give new insight into the development of novel therapeutics for NSCLC.

Sterically modulated silver(I) complexes of coumarin substituted benzimidazol-2-ylidenes: Synthesis, crystal structures and evaluation of their antimicrobial and antilung cancer potentials.

In this contribution, a series of sterically-encumbered coumarin substituted benzimidazole-based N-heterocyclic carbene (NHC) precursors (1-12) and their silver(I)-NHC complexes (13-24) are reported. Molecular structure of NHC precursors 8 and 12 and cationic complexes 15 and 16 was established by single crystal X-ray diffraction method. The silver(I) complexes demonstrated various significant intramolecular agostic-like interactions operating between the metal center and the hydrogen atoms of the substituents alongside a variety of feeble π-π stacking interactions. A distorted linear coordination geometry is documented at the silver(I) center with the anti-arrangement of the ligands. Further, the complexes demonstrated promising antibacterial properties against Gram positive and Gram negative bacterial strains, especially complex 18 displayed a minimum inhibitory concentration (MIC) of 2 and 4 µg/mL against S. aureus and E. coli, and P. aeruginosa, respectively. Furthermore, complexes 14, 15, 16 and 18 were found cytotoxic against the human lung cancer cell lines A549 and H1975 with the IC50 (concentration of the test sample required to kill 50% of the cell population) value under 10 µM, while mono-NHC complex 20 displayed a potential drug window with the IC50 of 13.7 ±â€¯2.70 and 14.5 ±â€¯1.20 µM against the cancer cell lines H1975 and A549, respectively. Notably, these complexes displayed relatively lesser cytotoxic behaviour against the normal skin fibroblast cell line, Hs68. All the NHC precursors displayed significantly lower biological activities compared with their respective complexes, indicating the utility of silver(I) ions in antimicrobial and antilung cancer applications.

In vitro assessment of Macleaya cordata crude extract bioactivity and anticancer properties in normal and cancerous human lung cells.

The purpose of this study is to assess the bioactivity and anticancer properties of Macleaya cordata crude extract in vitro using normal fetal lung fibroblast MRC5 and adenocarcinomic epithelial cell A549 as model systems,. Treatment of extract induced cell detachment, rounding, and irregularity in shape, in both normal and adenocarcinomic human lung cells, in accompanied of significant reduction in cell proliferation. The data indicated that necrosis appeared to be involved in compromising cell growth in both types of lung cells since membrane permeability and cell granularity were elevated. Although apoptosis was evident, the responses were differential in normal and diseased lung cells. Viability of treated MRC5 cells was reduced in a dose-dependent manner, demonstrating that the normal lung cells are sensitive to the extract. Surprisingly, A549 viability was slightly elevated in response to extract exposure at low concentration, implying that cells survived were metabolically active; the viability was reduced accordingly to treatment at higher concentrations. The present findings demonstrate that the crude extract of M. cordata contains agents affecting the functioning of normal and diseased lung cells in vitro. The observed cytotoxic effects against adenocarcinomic lung cells validate the potential of using M. cordata as herbal intervention in combined with conventional chemotherapy for lung cancer treatment.